An amide unit is a very common functional group and exhibits major features in several important natural products or artificial compounds. A number of compounds with the structure of an amide display a very important character in the synthesis of medicines. For example, these compounds are useful as intermediates or precursors in the synthesis of final medicines. For example, the N-acylalkylenediamines of formula (I') or (II') are amides and can be respectively used as the intermediates for the synthesis of the anti-hypertension medicines of formula (I) or (II). ##STR1##
Generally speaking, the synthesis of such type of anti-hypertension medicines is conducted by reacting the quinazolinyl chloride intermediate of formula (III) ##STR2##
with the N-acylalkylenediarnine intermediate of formula (I') or (II'), to obtain a compound of formula (I) or (II).
As to the synthesis of the intermediate of formula (III), i.e. 4-amino-2-chloro-6,7-dimethoxyquinazoline, DE 2 847 623 and J. Med. Chem. 1987, 30, 49 have fully disclosed the synthesis procedures.
There are a number of known methods for the synthesis of amides. For example, they can be produced by the reaction of amines with esters, which involves known, basic organic chemical reactions. Under heating conditions, the reaction of a primary amine and an ester can directly produce an amide bond. However, such a reaction mostly needs to be conducted in the presence of solvents. As to the amidation reaction of a secondary amine and an ester, it needs to be conducted under the catalysis of Lewis acids, strong bases or enzymes, in addition to the presence of solvents.
The conventional methods for direct conversion of carboxylic acids to amides require either a very high reaction temperature (over 190.degree. C.) or special coupling agents, such as carbodumides, phosphorus agents and uronium salts. These coupling agents require preparation and cause problems in isolation of the desired amidation products.
In recent years, several researchers have dedicated to use a variety of processes to synthesize new N-acylalkylenediarnine intermediates, in order to synthesize new anti-hypertension medicines. For example, DE 2 847 623 and J. Med. Chem. 1987, 30, 49 disclose: ##STR3##
Arch. Pharm. 1994, 327, 661 discloses: ##STR4##
Farmaco. 1996, 51, 551, J. Med. Chem. 1977, 20, 146 and U.S. Pat. No. 4,026,894 disclose: ##STR5##
Org. Prep. Proced. Int. 1976, 8, 85 discloses: ##STR6##
J. Med. Chem. 1986, 29, 19 discloses: ##STR7##
U.S. Pat. No. 4,093,726 discloses: ##STR8##
In view of the above, conventional processes for the preparation of N-acylalkylenediamine intermediates have the following characteristics:
(1) The processes use the corresponding organic acids as starting materials, activate the starting materials to form acyl chlorides or higher active intermediates such as anhydrides, then react the acyl chlorides or anhydrides with diamines to obtain the desired N-acylalkylenediamines. The reaction procedures of these processes are too complicated and the Yield: is low (about 40%-70%). Also, these processes may produce waste chemicals causing environmental problems.
(2) Since the reactivity of acyl chlorides or anhydrides is very high, one of the amino groups in the diamines used needs to be protected by hydrogen chloride, hydrogen brormide, acetic acid or a tertiary butyloxycarbonyl compound to prevent diamides formation. Subsequently, the deprotection step is required to obtain the desired N-acylalkylenediamines.
Therefore, the object of the present invention is to provide a process for the preparation of amides with simple steps and high Yield:, which simply reacts amines and carboxylic acids in the presence of silicon amines to form amides in situ. The process of the invention does not require the conversion of acids to alkyl esters, neither does it require high reaction temperatures or additional agents.